The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis
OncoTargets and Therapy
The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis
Ke-li liao 1
song huang 1
Yu-Peng Wu 0
0 Department of n eurosurgery, The second hospital of hebei Medical University , shijiazhuang, hebei, People's republic of china
1 Department of n eurosurgery, Zigong First People's hospital , Zigong, sichuan, People's republic of china
8 1 0 2 - l u J - 3 1 n o 7 0 2 . 6 4 . 9 5 . 7 3 y b / m o c . s s re . .vdoep lsyeon PowerdbyTCPDF(ww.tcpdf.org) Background: A combination of temozolomide (TMZ) and radiotherapy and subsequent adjuvant chemotherapy is the gold standard of treatment for glioblastoma (GB). Bevacizumab (BEV), a humanized monoclonal antibody that blocks the effects of vascular endothelial growth factor A, has produced impressive response rates for recurrent GB and has been approved as second-line therapy. The efficacy and safety of BEV in newly diagnosed GB are not known. Aim: This systematic meta-analysis was undertaken to evaluate the value of combination therapy involving BEV in newly diagnosed GB. Methods: Electronic databases were searched for eligible literature up to October 2017. Randomized controlled trials assessing the efficacy and safety of BEV in patients with newly diagnosed GB were included, of which the main outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). All the data were pooled with the corresponding 95% confidence intervals (CIs) using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated. Results: A total of six randomized controlled trials were included in this analysis. The experimental BEV group had significantly improved the overall PFS (OR =0.46, 95% CI =0.26-0.81, P=0.007), as well as PFS at 6 months (OR =3.47, 95% CI =2.85-4.22, P,0.00001) and PFS at 12 months (OR =2.02, 95% CI =1.66-2.46, P,0.00001), respectively. However, there were no significant differences in PFS at 24 months with BEV (OR =0.95, 95% CI =0.61-1.48, P=0.82). OS at 6 months (P=0.07) and 24 months (P=0.07) was not significantly improved with BEV in patients with newly diagnosed GB. However, the meta-analysis on the OS at 12 months showed differences with BEV (OR =1.24, 95% CI =1.03-1.50, P=0.02). Conclusion: Our study indicates that addition of BEV for newly diagnosed GB resulted in a superior PFS rate. However, the combination therapy involving BEV did not improve OS. Future investigations are needed to analyze whether BEV helps improve OS efficacy.
(anti-VEGF) agent, bevacizumab (BEV) serves as a
potentially therapeutic option for GB.6 Based on the promising
outcomes of two Phase II trials, the US Food and Drug
Administration (FDA) has approved BEV in the second-line
treatment of recurrent GB in 2009.14 The addition of BEV
produces impressive progression-free survival (PFS) and
response rate compared to standard treatment for recurrent GB,
while the value of BEV on OS is still a matter of debate.7–9
At the time of the approval of BEV in recurrent disease,
several randomized controlled trials (RCTs) were launched
to investigate the value of BEV in addition to the treatment
for newly diagnosed GB.10–15 Treatment combined with BEV
exhibited significant activity in PFS for newly diagnosed GB
patients, while further evaluation is needed to assess disease
progression after antiangiogenic therapy.
In order to make care for newly diagnosed GB more rational,
we conducted a meta-analysis of RCTs to evaluate the
therapeutic value of BEV compared with standard therapy (ST).
Studies that met the following criteria were included in the
meta-analysis: 1) the studies were designed as RCTs; 2) studies
focused on newly diagnosed GB treated with BEV; 3) the
outcomes of interest regarding the treatment efficacy (survival),
safety (adverse events [AEs]), and hazard ratios (HRs) with
corresponding 95% CIs were provided; 4) only the full texts
were included. The studies that did not meet the above
inclusion criteria were excluded from the meta-analysis.
Study quality was assessed using the Jadad seven-item scale
recommended by The Cochrane Handbook for Systematic Reviews
of Interventions. The Jadad seven-item scale was introduced to
evaluate the overall methodological quality of RCTs.
The data extraction was conducted independently by two
authors. Disagreement was revolved by consensus. The
main characteristics extracted from the selected studies were
the following: first author family name, publication year,
trial name, study design, sample size, and the outcomes of
interest (AEs, PFS, and OS). The corresponding hazard
ratios (HRs) with 95% confidence intervals (CIs) were used
to describe the main outcomes of the studies, including
OS, PFS, and AE data, and 95% CIs were calculated for
The main outcomes of the studies were OS, PFS, and AEs.
If HRs and corresponding 95% CIs were reported, the lnHRs
and the corresponding ln lower limits and ln upper limits
were used as data points in pooling analysis. While, if the
study did not provide HRs or 95% CIs, the only available
data were in the form of Kaplan–Meier (K–M) curves.
Survival data were extracted from the form of the K–M survival
curve, according to the methods described by Tierney et al.16
The I 2 statistical test was used to further examine statistical
heterogeneity between the trials.17 Studies with an I 2$50%
were considered to exhibit moderate and high
heterogeneity, and those with I 2,50% were considered to have low
heterogeneity.18 Summary HRs were calculated by using
fixed-effect models when there was low heterogeneity among
studies. Otherwise, random-effect models were used. A
P-value ,0.05 was considered to be statistically significant.
All analyses were conducted with Review Manager Version
5.3 software (Revman; The Cochrane Collaboration, Oxford,
UK). Findings of our meta-analysis are shown in forest plots.
The Begg’s test and the Egger’s test were used to evaluate
search results and characteristics of
A total of 214 studies were retrieved initially for evaluation.
Based on the criteria described in the “Methods” section,
10 publications were evaluated in more detail, but some did
not provide enough detail of the outcomes of two approaches.
Therefore, we had a final total of six RCTs10–15 assessing the
value of BEV in patients with newly diagnosed GB. The
search process is described in Figure 1.
All included papers in this study were based on
moderateto high-quality evidence. Table 1 describes the primary
characteristics of the eligible studies in more detail.
clinical and methodological
Pooled analysis of PFs comparing the addition of BeV
with the control group
Pooling the PFS data from five studies10,11,13–15 showed that
BEV prolonged the PFS (HR =0.69, 95% CI =0.63–0.77,
P,0.00001) compared with the control group (Figure 2).
subgroup analysis of PFs comparing the addition of
BeV with the control group
Overall, the six studies that reported data on PFS at different
months are shown in Figures 3–5. Pooled data showed that
the PFS data achieved advantage with BEV agents, with the
pooled OR being 3.47 (95% CI 2.85–4.22, P,0.00001) at
6 months (Figure 3); 2.02 (95% CI 1.66–2.46, P,0.00001) at
027 12 months (Figure 4); and 0.95 (95% CI 0.61–1.48, P=0.82)
..46 at 24 months (Figure 5). In other words, the addition of
.759 BEV agents increases the PFS.
/yb Pooled analysis of Os comparing the addition of BeV
.com with the control group
rsse . A random-effects model was used to pool the OS data.10,11,13–15
.vdoep lsyeon The pooled data showed that a BEV agent plus chemotherapy
w u did not improve the OS (HR =0.91, 95% CI =0.76–1.08,
//:ww lano P=0.28) than the control treatment (Figure 6).
th rp subgroup analysis of Os comparing the addition of
from oF BeV with the control group
edd Subgroup analysis of OS data at different months was
availloan able for all six RCTs.10–15 Analysis showed that the results
odw of OS at 6 months (HR =1.28, 95% CI =0.98–1.67, P=0.07)
yap (Figure 7) with BEV were no longer significant in patients
reh with newly diagnosed GB, while the meta-analysis on the
dnT OS at 12 months showed differences with BEV (HR =1.24,
tsae 95% CI =1.03–1.50, P=0.02) (Figure 8). However, OS at
rga 24 months still did not reach statistically significant difference
cnoT (HR =1.22, 95% CI =0.98-1.52, P=0.07) (Figure 9).
Pooled analysis of aes comparing the addition of
BeV with the control group
Due to the limited data in all studies, systematic
evaluations of AE data were not possible in this meta-analysis.
Gilbert et al13 report that toxicities, hypertension,
thromboembolic events, intestinal perforation, and neutropenia
were observed in the BEV group. Over time, patients treated
with BEV have an increased symptom burden following a
worse QoL, as well as debilitating neurological symptoms.
In Chinot et al,14 grade 3 or higher AEs (66.8% vs 51.3%)
were more frequent in the BEV group.
GB is the most frequent malignant brain tumor with a poor
prognosis. Patients with recurrent GBs have a poor OS,
and available therapies have a limited impact on prognosis.
Therefore, development of a new approach is essential to
improve the outcomes in patients with newly diagnosed GB.
In Phase III RCTs,3 the addition of TMZ to chemoradiotherapy
(CRT) and subsequent adjuvant chemotherapy has been the
standard therapy with newly diagnosed GB and is thought to
be the backbone for further understanding therapy choices.19
Research reports have shown that GB has multistep cytostatic
effects that alter neovascularization of brain tissue to form
new blood vessels, which may help slow tumor progression
and proliferation.20,21 VEGF is overexpressed in malignant
gliomas and has been used as a therapeutic target for brain
BEV, a humanized monoclonal antibody against the
VEGF ligand, has received FDA approval for recurrent
Chauffert et al, 201411
Balana et al, 201610
Carlson et al, 201512
Gilbert et al, 2014
Chinot et al, 2014
Herrlinger et al, 201615
GBMs in 2009.23–25 The results have suggested that a potential
benefit could be achieved by BEV for newly diagnosed
GB.26 To assess whether BEV would be safe and effective
for the treatment of newly diagnosed GB, we conducted
a meta-analysis to evaluate the value of therapy with the
combination of BEV.
All included studies chose OS and PFS as the primary
end points. At the time of disease progression, crossover
regimen may continue to benefit patients following an initial
response to therapy with or without BEV. Therefore, in newly
diagnosed GBs, the end point of PFS has beneficial effects
in evaluating the potential effects of combined treatment
with BEV than OS.13
Data from the trial of Carlson et al,12 showed that
compared with placebo plus TMZ and radiotherapy, the
combination using BEV did not improve OS, but increases
PFS, although it is statistically nonsignificant (P=0.39). In
the AVAglio and RTOG 0825 studies,13,14 the PFS was
significantly improved with the addition of BEV, but OS did
not show benefit.
In this study, we conclude that the combination of BEV
for newly diagnosed GB is beneficial in terms of prolonging
median PFS but not OS. Our results did not indicate any
benefit from BEV for newly diagnosed GB in terms of median
OS. The AVAglio, RTOG 082512, and GLARIUS13–15 trials
obtained similar results. In our analysis, the pooled analysis
did not show that the PFS benefit translates into OS
prolongation. As potential reasons for this observation, patients with
GB exhibited worse neurocognition and poor survival rate
with prolonged use of BEV, which might be caused by BEV
resistance. Resistance to chemotherapy was considered to
influence the effectiveness of BEV treatment for GB. As an
antiangiogenic (anti-VEGF) agent, BEV has been investigated
as complementary to standard chemotherapy to suppress
tumor growth.27 Due to the different angiogenesis pathways
of the VEGF genes, there may be benefit in continuing BEV
treatment even after resistance to chemotherapy.28–30
However, the potential antitumor effects underlying resistance to
antiangiogenic agents are yet to be fully evaluated. The point
of molecular signatures may reveal subsets of GBs that are
particularly sensitive or resistant to BEV. In additional
analyses of subgroups of patients based on different genetic
mutations, we may identify patients who had a selected survival
benefit response to BEV. Furthermore, BEV’s radiographic
effect has been reported to be associated with an increased
incidence of PFS. BEV stabilizes the blood–brain barrier,
minimizing the ability of the magnetic resonance imaging
(MRI) contrast agent gadolinium to reach the tumor, thus
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showing “improved” or “cleaner” MRIs, hence delaying the
BEV therapy does not have a place in ST with newly
diagdiagnosis of progression (a largely radiographic diagnosis)
nosed GB. We suggest that studies of correlative molecular
and consequently showing prolonged PFS. Moreover,
secondsignatures are needed to identify particular subgroups of
line crossover BEV therapy has been shown to play an
imporpatients who will receive benefit from the combination of
tant role in the OS. Therefore, there is much more detailed
BEV. Further research is needed to define the best treatment
knowledge on postprogression therapy. In GLARIUS,15
response with the lowest possible toxicity in selecting
suitpatients who received the crossover BEV therapies achieved
able patients with consideration for their complications and
a significant OS benefit compared with other BEV first-line
trials. The RPSFT analysis, which evaluated the influence of
crossover BEV treatment, suggested a significant OS benefit
of the combination therapy of BEV and thus indicates that
The authors report no conflicts of interest in this work.
BEV crossover may be associated with OS prolongation.15
To date, the mechanism of long-term BEV treatment has
not been established. Further studies of other physiological
molecularly defined subgroups may suggest a
potential marker panel for BEV, which would need more clinical
trials to clarify.
In previous studies, the serious AEs observed more
frequently in the BEV group included abdominal pain,
headache, fatigue, hypertension, diarrhea, neutropenia,
complications of wound healing, cerebral hemorrhage or
ischemia, gastrointestinal perforation, congestive heart
failure, and anemia.13,14 Due to the limited data shown in all
studies, systematic evaluations of AE data were not possible
in this meta-analysis. In a previous meta-analysis, BEV
therapy was not found to be associated with serious AEs for
newly diagnosed GB.31 However, the authors did indicate a
trend toward significance with respect to BEV treatment.31
In this systematic analysis assessing the value of BEV
in the treatment of newly diagnosed GB, there are some
limitations that should not be ignored. First, as only full texts
were included and this study was a study-level meta-analysis,
which resulted in imbalance between the two groups, clinical
heterogeneity among trials should be taken into consideration
in the interpretation of our findings. Second, most included
studies reported short-term survival rates within 2 years
of follow-up. There were insufficient data to determine
long-term survival rate. Further studies are needed to report
survival rates at 3 years or longer follow-ups. Third, as the
data on AEs in the included trials is limited, we did not
perform the analysis of AEs in this meta-analysis.
BEV treatment has a potential benefit in terms of PFS, but not
OS. The apparent lack of OS benefit is probably associated
with the confounding effects of crossover, although many
other explanations are possible. On the basis of all
available studies (AVAglio, RTOG 0825, and GLARIUS),13–15
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